The first description of a rare monogenic disease with polymicrogyria caused by a pathogenic variant in the gene WASF1 in monozygotic twins

Abstract

Neurodevelopmental disorder without speech and variable seizures (NEDALVS) is a rare autosomal dominant inherited disorder, characterized by motor development delay, mental retardation, wide-based gait, autism spectrum disorders and seizures. 
 Currently, fifteen cases of NEDALVS have been described worldwide.
 NEDALVS caused by mutations in the WASF1 gene, located on the long arm of chromosome 6. Nonsense-, missense-, frameshift mutations and large deletion have been described in WASF1 gene. 
 We present the clinical case of 9-year monozygotic NEDALVS twins, accompanied by cerebral pachygyria/polymicrogyria. DNA diagnostic was performed using full genome sequencing, followed by validation using Sanger sequencing. A previously described heterozygous pathogenic variant c.1516C>T (p.R506*) in the WASF1 gene was identified.
 We performed the results of a comparative analysis based on the literature and our patients. All patients had delayed motor and psycho-speech development, severe mental retardation was in 53% of cases, lack of speech — 18%, autistic manifestations and seizures — 41%, wide-based gait — 29%, strabismus and feeding problems — 35%.
 Conclusion. WASF1 gene mutations caused a rare form of mental retardation in children. We present the first case of NEDALVS in Russian Federation and the world’s first description of pachygyria in patients, caused by WASF1 gene mutations. The use of NGS as a first-line test for research and diagnostic of neurodevelopmental disorder is determined by their non-specific clinical features.